Publications by authors named "Jonathan C M Wan"

13 Publications

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COVIDReady2 study protocol: cross-sectional survey of medical student volunteering and education during the COVID-19 pandemic in the United Kingdom.

BMC Med Educ 2021 Apr 14;21(1):211. Epub 2021 Apr 14.

Nuffield Department of Primary Care Health Sciences, Medical Sciences Division, University of Oxford, Oxford, UK.

Background: The coronavirus disease 2019 pandemic has led to global disruption of healthcare. Many students volunteered to provide clinical support. Volunteering to work in a clinical capacity was a unique medical education opportunity; however, it is unknown whether this was a positive learning experience or which volunteering roles were of most benefit to students.

Methods: The COVIDReady2 study is a national cross-sectional study of all medical students at medical schools in the United Kingdom. The primary outcome is to explore the experiences of medical students who volunteered during the pandemic in comparison to those who did not. We will compare responses to determine the educational benefit and issues they faced. In addition to quantitative analysis, thematic analysis will be used to identify themes in qualitative responses.

Discussion: There is a growing body of evidence to suggest that service roles have potential to enhance medical education; yet, there is a shortage of studies able to offer practical advice for how these roles may be incorporated in future medical education. We anticipate that this study will help to identify volunteer structures that have been beneficial for students, so that similar infrastructures can be used in the future, and help inform medical education in a non-pandemic setting.

Trial Registration: Not Applicable.
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http://dx.doi.org/10.1186/s12909-021-02629-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045566PMC
April 2021

The future of liquid biopsy.

Lancet Oncol 2020 12;21(12):e550

Zuckerman Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30687-2DOI Listing
December 2020

Correlating Radiomic Features of Heterogeneity on CT with Circulating Tumor DNA in Metastatic Melanoma.

Cancers (Basel) 2020 Nov 24;12(12). Epub 2020 Nov 24.

Department of Radiology, University of Cambridge, Cambridge CB2 0QQ, UK.

Clinical imaging methods, such as computed tomography (CT), are used for routine tumor response monitoring. Imaging can also reveal intratumoral, intermetastatic, and interpatient heterogeneity, which can be quantified using radiomics. Circulating tumor DNA (ctDNA) in the plasma is a sensitive and specific biomarker for response monitoring. Here we evaluated the interrelationship between circulating tumor DNA mutant allele fraction (ctDNA), obtained by targeted amplicon sequencing and shallow whole genome sequencing, and radiomic measurements of CT heterogeneity in patients with stage IV melanoma. ctDNA and radiomic observations were obtained from 15 patients with a total of 70 CT examinations acquired as part of a prospective trial. 26 of 39 radiomic features showed a significant relationship with log(ctDNA). Principal component analysis was used to define a radiomics signature that predicted ctDNA independent of lesion volume. This radiomics signature and serum lactate dehydrogenase were independent predictors of ctDNA. Together, these results suggest that radiomic features and ctDNA may serve as complementary clinical tools for treatment monitoring.
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http://dx.doi.org/10.3390/cancers12123493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759931PMC
November 2020

Survival Outcomes of Early versus Deferred Cystectomy for High-Grade Non-Muscle-Invasive Bladder Cancer: A Systematic Review.

Authors:
Jonathan C M Wan

Curr Urol 2020 Jun 23;14(2):66-73. Epub 2020 Jun 23.

School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Background: Studies report that survival outcomes in patients with non-muscle-invasive bladder cancer (NMIBC) are worse when cystectomy is delayed. However, no systematic evidence is available.

Objective: The aim of this study was to systematically review the literature to compare the long-term survival outcomes of patients with high-grade NMIBC (T1G3, including carcinoma in situ) who have early cystectomy compared to deferred radical cystectomy post-diagnosis.

Materials And Methods: A systematic review was carried out by searching MEDLINE and related databases (Google Scholar, National Health Service Evidence) for all relevant studies published from 1946 to present. Additional studies were identified through following the references of relevant papers. Studies were included if they met the following criteria: inclusion of at least 30 patients having high-grade NMIBC, 2 groups treated with either early or deferred cystectomy with a clear temporal cut-off between groups and reported data on survival rate of at least 5 years.

Results: Literature was systematically reviewed, and 10 studies were included, totaling 1,516 patients who underwent either primary cystectomy or deferred cystectomy. It was found that patients who underwent early cystectomy show improved 5- to 10-year cancer-specific survival (relative risk = 0.81, p = 0.029) suggesting a significant survival benefit when compared to deferred cystectomy.

Conclusions: This study provides systematically gathered evidence showing benefit of early cystectomy. Despite this result, radical cystectomy greatly impairs quality of life and represents overtreatment for a significant minority. This result highlights the importance of a decisive treatment plan to minimize treatment delay.
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http://dx.doi.org/10.1159/000499257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390979PMC
June 2020

ctDNA monitoring using patient-specific sequencing and integration of variant reads.

Sci Transl Med 2020 06;12(548)

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >10 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
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http://dx.doi.org/10.1126/scitranslmed.aaz8084DOI Listing
June 2020

Detection of ctDNA from Dried Blood Spots after DNA Size Selection.

Clin Chem 2020 May;66(5):697-705

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

Background: Recent advances in the study and clinical applications of circulating tumor DNA (ctDNA) are limited by practical considerations of sample collection. Whole-genome sequencing (WGS) is increasingly used for analysis of ctDNA, identifying copy-number alterations and fragmentation patterns. We hypothesized that low-depth/shallow WGS (sWGS) data may be generated from minute amounts of cell-free DNA, and that fragment-size selection may remove contaminating genomic DNA from small blood volumes. Dried blood spots have practical advantages for sample collection, may facilitate serial sampling, and could support novel study designs in humans and animal models.

Methods: We developed a protocol for the isolation and analysis of cell-free DNA from dried blood spots using filter paper cards and bead-based size selection. DNA extracted and size-selected from dried spots was analyzed using sWGS and polymerase chain reaction (PCR).

Results: Analyzing a 50 μL dried blood spot from frozen whole blood of a patient with melanoma, we identified ctDNA based on the presence of tumor-specific somatic copy-number alterations, and found a fragment-size profile similar to that observed in plasma DNA. We found alterations in different chromosomes in blood spots from 2 patients with high-grade serous ovarian carcinoma. Extending this approach to serial dried blood spots from mouse xenograft models, we detect tumor-derived cell-free DNA and identified ctDNA from the originally grafted ascites.

Conclusion: Our data suggest that ctDNA can be detected and monitored in dried blood spots from archived and fresh blood samples, enabling new approaches for sample collection and novel study/trial designs for both patients and in vivo models.
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http://dx.doi.org/10.1093/clinchem/hvaa050DOI Listing
May 2020

Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors.

Genome Med 2020 02 28;12(1):23. Epub 2020 Feb 28.

Hutchison/MRC Research Centre, University of Cambridge, Cambridge, CB2 0QQ, UK.

Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established.

Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine.

Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings.

Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.
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http://dx.doi.org/10.1186/s13073-020-00723-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048087PMC
February 2020

Serum Vitamin D and Magnesium levels in a psychiatric cohort.

Psychiatr Danub 2019 Sep;31(Suppl 3):221-226

University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Background: Both Vitamin D deficiency and magnesium deficiency have an increased prevalence and have been associated with an increased risk of and increased severity of symptoms in both depression and schizophrenia (Boerman 2016, Tarleton & Littenberg 2015). This effect appears more pronounced in younger populations and is often apparent from the time of initial diagnosis and is present with adjustment for confounding factors. Thus, the evidence suggests that Vitamin D and magnesium deficiency reflects not only dietary or somatic aspects of health but also may have a role in the pathophysiology of depression and schizophrenia.

Subjects And Methods: A single site audit of serum Vitamin D and magnesium levels in patients at an Acute Day Treatment Unit was carried out. Blood tests were performed on admission and analysed in house. Data were collected between April - June 2019 and was analysed subsequently, as described below (n=73).

Results: Our data show that our psychiatric day treatment unit cohort (n=73) had a higher proportion of vitamin D deficiency (52%) than the general population (40%), although due to the limited sample size this was not significant (p=0.22, Chi-squared test). The percentage of patients who were magnesium deficient was 78.6% (n=22/28). However, the F60 subgroup of patients with personality disorders showed a high prevalence of vit D deficiency (p=0.07), highlighting a trend towards significance despite the limited size of this subgroup.

Conclusions: We carried out a single-site audit of serum vitamin D and magnesium levels in a psychiatric day unit population in order to assess the extent of vitamin deficiency in such patients. These data indicate that that the proportion of patients with vitamin D deficiency is higher than in the general population. Further larger analysis is needed to establish the statistical significance of these data and whether treatment with vitamin D supplementation improves outcomes.
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September 2019

"Hey CIRI, What's My Prognosis?"

Cell 2019 07;178(3):518-520

Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Although serial tumor assessments are increasingly performed through imaging and molecular approaches, such evaluations are often considered in isolation, as robust frameworks for integrating multiple biomarkers are currently lacking. Thus, in this issue of Cell, Kurtz et al. present a method (termed CIRI) that integrates pre-treatment and on-treatment risk factors for accurate outcome prediction.
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http://dx.doi.org/10.1016/j.cell.2019.07.005DOI Listing
July 2019

Enhanced detection of circulating tumor DNA by fragment size analysis.

Sci Transl Med 2018 11;10(466)

Cambridge University Hospitals NHS Foundation Trust, CB2 0QQ Cambridge, UK.

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
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http://dx.doi.org/10.1126/scitranslmed.aat4921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483061PMC
November 2018

Student-led leadership training for undergraduate healthcare students.

Leadersh Health Serv (Bradf Engl) 2017 10 25;30(4):428-431. Epub 2017 Sep 25.

St George's Hospital, London, UK.

Purpose Effective clinical leadership is crucial to avoid failings in the delivery of safe health care, particularly during a period of increasing scrutiny and cost-constraints for the National Health Service (NHS). However, there is a paucity of leadership training for health-care students, the future leaders of the NHS, which is due in part to overfilled curricula. The purpose of this study was to assess the impact of student-led leadership training for the benefit of fellow students. Design/methodology/approach To address this training gap, a group of multiprofessional students organised a series of large-group seminars and small-group workshops given by notable health-care leaders at a London university over the course of two consecutive years. Findings The majority of students had not previously received any formal exposure to leadership training. Feedback post-events were almost universally positive, though students expressed a preference for experiential teaching of leadership. Working with university faculty, an inaugural essay prize was founded and student members were given the opportunity to complete internships in real-life quality improvement projects. Originality/value Student-led teaching interventions in leadership can help to fill an unmet teaching need and help to better equip the next generation of health-care workers for future roles as leaders within the NHS.
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http://dx.doi.org/10.1108/LHS-03-2017-0018DOI Listing
October 2017

Liquid biopsies come of age: towards implementation of circulating tumour DNA.

Nat Rev Cancer 2017 04 24;17(4):223-238. Epub 2017 Feb 24.

Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.
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http://dx.doi.org/10.1038/nrc.2017.7DOI Listing
April 2017

Student-run medical journals: Supporting the future of medical academia.

Med Teach 2016 Oct 30;38(10):1072. Epub 2016 Aug 30.

a School of Clinical Medicine, University of Cambridge , Cambridge , UK.

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http://dx.doi.org/10.1080/0142159X.2016.1219025DOI Listing
October 2016